Nephrol Dial Transplant (2009) 24: 1253–1259 doi: 10.1093/ndt/gfn643
Advance Access publication 26 November 2008
Non-phenacetin analgesics and analgesic nephropathy
Clinical assessment of high users from a case-control study [1]∗Paul Michielsen
1, Lothar Heinemann
2, Michael Mihatsch
3, Peter Schn¨ulle
4, Helmut Graf
5and
Karl-Martin Koch
6∗This publication is dedicated to the memory of Professor Fokke J. van der Woude (1953–2006).
1Faculty of Medicine, University of Leuven, Belgium,2Centre for Epidemiology & Health Research, Berlin, Germany,3Institute of
Pathology, University Hospital, Basel, Switzerland,4Medical Faculty of Mannheim, University of Heidelberg, Germany, 5Krankenanstalt Rudolfstiftung, Vienna, Austria and6Clinic for Nephrology, Hannover Medical School, Germany
Abstract
Background. A recent large-scale case-control study on
analgesic nephropathy (SAN) [1] found no increased risk of end-stage renal disease (ESRD) in users of combined or single formulations of phenacetin-free analgesics. In a subgroup of 22 high users, however, a dose-dependent in-creased risk was found, which raised the question if these patients presented or not with analgesic nephropathy (AN).
Methods. The individual questionnaires of this subgroup
of high users were reviewed, and the total lifetime intake of different types of analgesics was calculated. For evidence of AN, the following data were considered: (1) the amount and type of analgesics consumed, (2) the cause of ESRD, as diagnosed by the nephrologist in charge of the patient and (3) renal imaging and other relevant laboratory data.
Results. This group of ESRD patients consumed on
av-erage 7.8 kg of antipyretic analgesics (range 30.8–2.7 kg) over an average of 21.5 years (range 35–6 years). Single analgesics were exclusively used by 12 patients (54.5%) and combined analgesics by 5 patients (22.7%), while 5 patients used both. None of the patients was diagnosed as having AN, and a review of the questionnaires did not disclose evidence suggestive of AN. The possibility that, irrespective of AN, the analgesic (ab)use contributed to the progression of existing renal diseases cannot be answered in the absence of well-defined criteria. The data supporting the existence of such an analgesic-associated nephropathy (AAN) are, however, not consistent and most likely due to confounding by indication.
Conclusion. In a group of ESRD patients with high use of
non-phenacetin analgesics, no evidence of AN was found. There is no evidence that (ab)use of analgesics or NSAIDs other than phenacetin leads to a pathologically or clinically defined renal disease that could be named AN or AAN.
Correspondence and offprint requests to: Paul Michielsen, Acacialaan 54,
Herent B3020, Belgium. E-mail: paul.michielsen@med.kuleuven.be
Keywords: analgesic-associated nephropathy; analgesic
nephropathy; combined analgesics; NSAID; phenacetin
Introduction
The nephrotoxicity of analgesics first came under attention by the observation of a large number of ESRD cases in patients abusing analgesic mixtures containing phenacetin. This new disease was named phenacetin nephropathy. The exclusive role of phenacetin as cause of analgesic nephropa-thy (AN) was later challenged, first by the group of Kincaid-Smith [2], later by De Broe and Elseviers [3,4]. This re-sulted in a redefinition of AN as ‘a disease resulting from the habitual consumption over several years of a mixture containing at least two antipyretic analgesics and usually codeine or caffeine’. This new definition gained credibility after endorsement in 1996 by a Position Paper of the pres-tigious National Kidney Foundation [5]. Notwithstanding the questionable nature of the data supporting this new def-inition [6–9], it was accepted without restriction by lead-ing nephrologists [10], which resulted in an official state-ment of the professional German-speaking associations of Nephrology at their 1996 Congress in Berlin [11]. The con-troversy persisted, however, mainly because of the difficulty in excluding the previous phenacetin intake [12,13]. This resulted in the setup of a large-scale case-control study in Germany and Austria [study on analgesic nephropathy (SAN)], its main objective being the control of such bias by including only patients younger than 50 years. The pro-tocol of the study was published in detail [14], and in the recently published results [1] no evidence of an increased ESRD risk was found in users of combined or single formu-lations of phenacetin-free analgesics. In a subgroup of high users, however, a dose-dependent significantly increased risk of ESRD was found (Table 1). The present study was undertaken at the request of the SAN supervising Scientific Advisory Committee (SAC) to examine the clinical signif-icance of this finding, and more specifically to determine if C
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Table 1. Adjusted relative risk of ESRD by increasing cumulative lifetime
dose of analgesic use at index date 3 (5 years before ESRD)a
Grams Cases Controls OR (95% CI) Low use 546 2030 1.00 (referent)
<500 278 1365 0.75 (0.64–0.88) 501–1000 41 133 1.10 (0.77–1.59) 1001–1500 10 47 0.76 (0.38–1.52) 1501–2000 6 19 1.03 (0.40–2.62) 2001–2500 4 9 1.50 (0.48–4.74) 2501–3000 3 8 1.35 (0.37–4.94) ≥3001 19 11 6.02 (2.83–12.81
aData from the SAN study [1]. Reproduced with permission.
in this subgroup of high users ESRD was due to AN and re-lated to heavy consumption of mixed antipyretic analgesics as defined in [5].
Methods
In the SAN study, all antipyretic analgesics, non-steroidal anti-inflammatory agents (NSAIDs) and additives such as caffeine and codeine are included in the calculation, and the consumption is calculated at different time intervals before ESRD. In order to minimize the risk of confounding by indication, the cumulative lifetime consumption until 5 years before admission for dialysis (index date 3) was selected for the final analysis. As shown in Table 1, the so-defined consumption exceeded 2500 g in 22 cases. As the present study is aimed at examining the evidence of AN in this subgroup of 22 high consumers, the analgesic intake was recalculated to bring it in line with the definition of classical AN [5,15]. The following criteria were applied: 1. The total lifetime intake of analgesics, until admission
for dialysis (index date 1), was taken into account. 2. Only antipyretic analgesics (ASA, salicylates,
amin-ophenazone, acetaminophen, etc.) were considered; NSAIDs such as diclofenac, ibuprofen, naproxen, etc. were not included.
3. Combined analgesics (Combi) were defined as the com-bination of at least two antipyretic analgesics.
4. The intake of caffeine, codeine and other additives was excluded from the calculation of the analgesic intake. 5. For total intake calculation, only the intake exceeding
6 months was considered. Occasional intakes for minor transitory discomforts were not included.
Criteria for diagnosis of AN
The questionnaires completed by the interviewers and the physicians responsible for the dialysis of these 22 cases were further reviewed for evidence of AN by one of the authors (P.M.). As no autopsy data were available on these 22 cases, the diagnosis of AN was evaluated on the following data.
1. The cause of the ESRD, as estimated by the physician in charge of the patient.
Table 2. Number of patients in each category of analgesic consumption,
calculated at index 3 (5 years before ESRD), and at index 1 (at admission for dialysis)
Grams All analgesicsa
index 3 All analgesicsb index 1 Antipyretic analgesicsb index 1 2501–3000 3 0 2 3001–3500 5 2 1 3501–4000 2 4 3 4001–5000 4 3 3 5001–6000 2 0 1 >6000 6 13 12
aData from the SAN study [1]. bData obtained from the questionnaires.
2. Imaging data compatible with papillary necrosis [16]. 3. Detailed history of past (ab)use of antipyretic analgesics.
Results
Analgesic intake
As shown in Table 2, the inclusion in the calculation of the last 5 years before ESRD markedly increased the estimated lifetime consumption, but the strict restriction to antipyretic analgesics had only a marginal effect.
The lifetime consumption of antipyretic analgesics by these 22 cases averaged 7.8 kg (range 30.8–2.7), which is within the range of abuse reported as having induced AN. In Table 3, the patients/cases are separated in three groups according to the type of antipyretic analgesics consumed: only five patients had used exclusively combination for-mulations (Group I) and their average intake was 12.6 kg (range 30.8–2.7). Another five patients had used both single and combination formulations (Group II), with an average intake of 5.4 kg (range 7.5–4.1). Single preparations were used by 12 cases (Group III) and their average intake was 6.8 kg (range 19.2–2.9). NSAIDs were taken by seven patients: mefenamic acid by patients Id, Ie, IIc; ibuprofen by patients IIb, IIIa, IIId; diclofenac by patient IIIe (data not shown).
The compulsive daily intake of a large number of tablets over a prolonged period of time is a characteristic of phenacetin abuse [17]. In our patients, a continuous daily intake during 1 year or more was only found in three users of combined analgesics and eight users of single analgesics and the daily intake of tablets was much lower than reported for phenacetin-containing Combis (Table 3).
Diagnosis of AN
For a study aimed at evaluating the causal nature of a re-lationship between high intake of combined analgesics and AN, an unequivocal definition of AN and reliable criteria of diagnosis are essential. Based on autopsy observations in patients abusing phenacetin-containing mixed analgesics, AN was defined as characterized by papillary necrosis and secondary parenchymal lesions. This papillary necrosis is linked to the presence of capillary sclerosis, a specific
Non-phenacetin analgesics and analgesic nephropathy 1255
Table 3. Lifetime antipyretic analgesic consumption for users of Combi(I), mono(III) or both (II)
Antipyretic analgesics
Combinations Single products
Cases Diagnosis Gram Tablets/day Days/year Years Gram Tablets/day Days/year Years
Ia Unclear 30 812 6 365 32
Ib Polycystic kidneys 12 318 15 365 6
Ic Unclear 10 767 8 365 11
Id Polycystic kidneys 6 464 3 144 34
Ie Unclear 2 658 3–4 12–30 15
IIa Diabetic nephropathy 803 3–4 72–208 7 6 721 2–10 156–208 24
IIb Diabetic nephropathy 5 254 4 108 24 875 3 25 24
IIc Unclear 234 2 10 28 4 858 3 10–56 35
IId Focal glomerulosclerosis 1 002 4 24 24 3 080 4 48 26
IIe Diabetic nephropathy 1 390 2 12–30 30 2 684 2 12–90 30
IIIa Diabetic nephropathy 19 208 1–10 14–365 16
IIIb Unclear 14 933 2–10 6–365 14
IIIc Diabetic nephropathy 6 879 2–3 7–365 28
IIId Polycystic kidneys 6 547 2 365 19
IIIe Diabetic nephropathy 6 436 2–3 42–365 25
IIIf IgA nephropathy 6 193 4–2 365 20
IIIg Lupus nephritis 4 668 2–4 36–104 19
IIIh Diabetic nephropathy 3 689 1–3 24–365 30
IIIi Amyloidosis 3 628 2 156 25
IIIj Malignant hypertension 3 503 3–4 182 17
IIIk Glomerulonephritis 3 380 3 365 7
IIIl Renal infarction 2 870 2 4–147 20
Cause of ESRD as reported in the medical questionnaire.
lesion of the capillaries in the papillae and the mucosa of the pyelon and ureter. In the clinical setting, as substitute for a pathological diagnosis, a CT scan finding of bilater-ally decreased renal mass combined with bumpy contours and, in particular, papillary calcifications became accepted as diagnostic of AN [18,19]. Such renal lesions have been claimed to result from the abuse of combined analgesics with or without phenacetin [5,15,16].
The diseases considered responsible for ESRD are men-tioned in Table 3. In 17 patients a clear diagnosis is indi-cated, consistent with the progression to ESRD; for five cases the diagnosis was reported as unclear, but none of the patients was diagnosed as presenting AN. In addition to diabetic nephropathy, which was reported as responsi-ble for ESRD, patient IIIe had undergone a right nephrec-tomy for nephrolithiasis and pyonephrosis. In the absence of computer tomography, available echography data were reviewed for evidence suggesting papillary necrosis. None of the patients presented small indented kidneys with pap-illary calcifications (Table 4).
The clinical data of the cases with unclear diagnosis were as follows:
Case Ia is a 44-year-old woman who had taken com-bined analgesics for more than 30 years. She was a regular heroin and cocaine user for 25 years. The asso-ciation of proteinuria>2 g/24 h, a rapidly progressing renal failure and a biopsy finding of extreme tubular atrophy with interstitial fibrosis may be suggestive of ‘heroin nephropathy’. Echography did not suggest AN. Case Ic is a 46-year-old woman who started tak-ing combined analgesics at age 35 for prevention of
headache. There are inconsistencies in the medical his-tory as reported in the questionnaire. Objective data are scarce. Proteinuria is indicated as positive but without mentioning the degree. Echography disclosed small bumpy kidneys without calcifications. The following ESRD risk factors were present: hypertension, obesity (BMI 33), heavy smoker since age 17. The available data are insufficient to eliminate or confirm a diagnosis of AN.
Case Ie is a 42-year-old patient with a long-standing history of kidneys reduced in size, proteinuria, hyper-tension and toxaemia of pregnancy. There are no rea-sons to suspect AN. This patient also consumed 799 g of mefenamic acid over 26 years.
Case IIc is a 47-year-old woman with a long-term his-tory of intermittent use of various analgesics. She pre-sented hypertension and proteinuria>2 g/24 h. There are no reasons to suspect AN. This patient consumed 1032 g of mefenamic acid over 24 years.
Case IIIb is a 44-year-old man with insulin-dependent diabetes mellitus since the age of 3 years. He had a heart transplant and was suspected of cyclosporine toxicity.
Discussion
The data from the study questionnaires are unequivocal: In that none of the 22 patients in this group of high analgesic users was AN diagnosed by the referring nephrologists.
P.
Michielsen
et
al
.
Table 4. Clinical characteristics and risk factors for ESRD
Proteinuria Echography Smoking
Case Sex Intake of antipyretic
analgesics (g)
<2 g >2 g Reduced size Bumpy contour
Papillary calcifications
Hypertension Body mass
index
Ever Still
smoking
Packs/year
Ia F 30 812 Positive + − − + 23.14 Yes Yes 60
Ib F 12 318 Negative − − − + 26.26 Yes Yes 15.5
Ic F 10 767 +? +? + + − + 33.02 Yes Yes 28
Id M 6 464 Not available − − − + 22.63
Ie F 2 658 Positive + − − + 22.28 Yes 13.5
IIa M 7 524 Positive − + − + 22.41
IIb F 6 129 Not available − − − − 33.95 Yes 4.5
IIc F 5 092 Positive + − − + 25.22 Yes 0.25
IId M 4 082 Positive − − − + 21.43 Yes Yes 18.75
IIe M 4 074 Positive + − + + 19.34 Yes Yes 18
IIIa M 19 208 Positive Not available + 23.29 Yes Yes 33
IIIb M 14 933 Not available Not available + 23.37 Yes Yes 20
IIIc M 6 879 Positive − − − + 28.58 Yes 57.5
IIId M 6 547 Negative − − − + 25.93
IIIe F 6 436 Positive − − − + 31.20
IIIf M 6 193 Positive + − − + 36.59
IIIg F 4 668 Positive + − − + 23.34
IIIh M 3 689 Positive − − − + 29.63 Yes 18
IIIi F 3 628 Not available + − − + 14.82
IIIj M 3 503 Positive + − − + 24.49 Yes Yes 11
IIIk M 3 380 Positive + − − + 30.78
IIIl M 2 870 Negative − − − + 32.41 Yes 14
Non-phenacetin analgesics and analgesic nephropathy 1257 Has the diagnosis of AN been missed? Without autopsy
and without a CT scan this cannot be excluded, but in most patients there was clear evidence of another diagnosis, and in the patients with unclear diagnosis there was no evidence of papillary necrosis. A missed diagnosis of AN is unlikely for the following additional reasons:
• It is true that a clinical diagnosis of AN can be difficult, but in most studies claiming the toxicity of combined analgesics, the diagnosis of AN was also a clinical diag-nosis. It is unlikely that the nephrologists in charge of the patients would have lost their diagnostic skills, especially in Germany and Austria, countries with a high degree of awareness of AN among both the medical profession and the public.
• Analgesic intake did not correspond to the pattern deemed responsible for AN.
• In ESRD patients without clear diagnosis, a recent large-scale epidemiological study concluded that CT findings similar to those described by De Broe [18] were present only in a minority of heavy analgesic users [20], partic-ularly when phenacetin intake was excluded. The data from the present study are consistent with this conclu-sion.
• Also consistent with our study are the results of a population-wide case-control study in Sweden [21]. In this study, AN nephropathy as described by Elseviers and De Broe [18] was not found in patients with newly diagnosed renal failure.
• At the request of the SAN supervising scientific com-mittee, Mihatsch conducted in 2006 an exact replica-tion of his autopsy study performed in 1978–1980 in Basel [22]. The conclusion of this new study was that AN had disappeared [23]. It is unlikely that AN would have disappeared in Basel, but not in Germany and Austria.
Altogether, these arguments lead to the conclusion that the diagnosis of the referring physicians can be assumed to be correct and that the dose-dependent correlation found in the SAN study between high analgesic intake and ESRD was not due to AN. This, however, raises the question of the adequacy of the design of the SAN study. The ti-tle of the SAN study [1] suggests that it is only relevant to young age, as previous phenacetin (ab)use was elimi-nated by setting the age limit at 50 years. Did this age limit preclude the necessary massive consumption of analgesics and/or was the duration of observation sufficient to develop AN?
In most studies the cut-off point, defining the cumulative intake of analgesics correlated with an increased risk of AN, is 1 kg or 5000 pills lifetime use [19]. In the subgroup of high users investigated in the present study, the lowest lifetime intake was 3 kg, the maximum 30 kg and the dura-tion of abuse varied between 6 and 32 years. The age limit of 50 years was obviously more than adequate to allow for the massive consumption of analgesics reported as having caused AN.
The second question concerns the delay needed for the development of AN. In the definition of AN as a con-sequence of abuse of unspecified mixed antipyretic anal-gesics, it is assumed that the earlier observed phenacetin
toxicity was only part of a broader toxicity involving all mixed antipyretic analgesics. If this hypothesis were cor-rect, the massive use of combined analgesics could be ex-pected to induce the same lesions within the same time limit as if these combined analgesics contained phenacetin. As long as phenacetin-containing analgesics were still used, AN was a disease of middle age. Autopsy data from Basel [24] indicate that in the years 1948–1957, the maximal in-crease in the number of cases of chronic interstitial nephritis occurred in the age group of 31–40 years. Australian data published in 1970 [2] indicate that more than half of the patients with AN were below 50 years of age. The obvi-ous explanation for the present-day finding of AN as a disease of older age is that these cases, as seen today, are only late consequences of previous phenacetin abuse. This is consistent with the parallel modification of the autopsy findings. As described by Mihatsch, the normal sized kid-neys shedding necrotic papillae, routinely found at autopsy in the sixties, evolved progressively to the present-day find-ing of small bumped kidneys with papillary calcifications [25,26].
It can be concluded that the relevance of the SAN study was not limited to younger age and that it was adequate to detect AN if it had occurred. Taken together with the disappearance of AN from the autopsy studies in Basel, the present study leads to the inescapable conclusion that AN has disappeared with the ban of phenacetin and is no longer a public health problem. The term AN was introduced to include unspecified antipyretic analgesics or a combina-tion thereof as causal factors. As there is no evidence to support this extension, AN should be renamed ‘phenacetin nephropathy’.
In the SAN study, as in most epidemiological studies on the nephrotoxic role of analgesics, the end-point is not AN but ESRD. In the absence of validation of evidence of AN, the term ‘analgesic-associated nephropathy’ (AAN) is used in most of these studies and, besides AN, a con-tribution to the progression of existing renal diseases has been considered as possible. This possibility was most often considered for acetaminophen [21,27,28], but was not con-firmed in other studies [1,29]. However, as acetaminophen is recommended as the analgesic of choice in patients with renal disease [5], there is an increased risk of confounding by indication. The inconsistency of the data and the risk of bias have led to consider the evidence as inconclusive in several reviews [15,30,31].
The inconsistency of the data when individual analgesics are considered has led to a further enlargement of the defi-nition of AAN, including not only single or combined anal-gesics but also NSAIDs as contributing to the development or the progression of chronic renal disease of whatever aetiology [19]. All analgesics and NSAIDs are inhibitors of cyclooxygenase (COX), and it is tacitly assumed that they could therefore share the same toxicity for the kid-ney. It is beyond doubt that all analgesics could influence renal function. However, using COX inhibition as a com-mon link to consider together different analgesic drugs, ig-nores that there are different COXs and that the selectivity and activity of the inhibition differ from drug to drug (re-view in [32]). Furthermore, COX inhibition can have pos-itive as well as negative aspects. For the evaluation of the
possible effects of COX inhibition on existing renal dis-eases, different influences should be considered.
1. The influence on homeostasis: five different pros-taglandins play a major role in the regulation of var-ious aspects of renal function [33]. In the presence of reduced renal perfusion, especially in the elderly, COX-2 inhibition can lead to acute renal failure. The risk will be dependent on the inhibition ratio COX-2/COX-1 for the drug considered. As salicylic acid and acetyl salicylic acid are highly selective for COX-1, their influence on renal homeostasis will be negligible. Similarly, acetaminophen does not significantly inhibit either COX-1 or COX-2 but mainly COX-3, which is only present in the brain [32]. This influence on the homeostasis is drug specific and not common to all COX inhibitors. It is, however, not always negative as illustrated by the control of Bartter’s syndrome by in-domethacin administration [34].
2. The influence on pathological processes: Up-regul-ation of the expression of COX-1 and COX-2 is a response of the kidney to various aggressions, and especially COX-2 expression is increased in the macula densa and in some glomerular structures [35]. Influence of cyclooxygenase inhibitors can therefore be expected. One of the first re-ported examples of such an influence is the decrease of proteinuria under treatment with indomethacin [36,37]. This reduction is not only related to a reduction of the glomerular filtration but also to a restoration of the size-selectivity barrier [38]. These earlier clinical observa-tions are now supported by consistent experimental data [35,39–45]. In contrast with the majority of these ex-periments showing an improvement in the renal injury, COX-2 inhibition increased proteinuria and interfered with the healing process in a model of spontaneously recovering glomerulonephritis induced by anti-Thy1.1 [46].
Analgesics can also induce drug-specific adverse effects, unrelated to COX inhibition. Occasional hypersensitivity and interstitial nephritis can also occur in antipyretic anal-gesics as a drug-specific complication. Some NSAIDs, mainly fenoprofen, can in rare cases induce a nephrotic syndrome with a typical pathological picture of intersti-tial nephritis [47]. If these specific diseases occur super-imposed on existing renal diseases, they could influence the progression to ESRD, without loosing their identity. Bringing these specific diseases together with AN under the non-specific common name of AAN could only result in confusion.
In summary, the simplistic hypothesis of a contribution to the progression of existing renal diseases, common to all analgesics or NSAIDs, does not fit in with the clini-cal and experimental data. The influence of Cox inhibitors on the progression of existing renal diseases is a complex process with positive and negative aspects, without a com-mon pathological or clinical definition. In the absence of well-defined criteria, the SAN study as well as the earlier epidemiologic studies does not provide convinc-ing evidence justifyconvinc-ing overstretchconvinc-ing the concept AN to include all possible negative effects of analgesics and
NSAIDs, and consequently the concept of AAN should be reconsidered.
Conclusion
The present study failed to find evidence that AN was the cause of ESRD in the group of high users of single or com-bined analgesics reported in the SAN study. These findings support the conclusion [23] that AN should be renamed phenacetin nephropathy. Furthermore, there is no sound theoretical or clinical justification for maintaining the name AAN for an entity including, besides phenacetin nephropa-thy, a contribution by single or combined analgesics and NSAIDs to the development or the progression of chronic renal disease of whatever aetiology.
Acknowledgements. Table 1 is reproduced from reference [1] under the terms of Biomed Central’s Open Access Charter. The authors are indebted to Karin Thiele for review and correction of the paper.
The present study is based on data from a case-control study on anal-gesics and nephropathy (SAN) [1], details of which can also be found on the SAN website: http://www.san-study.com. The SAN study was ini-tiated at the initiative of the German regulating authorities (BfArM); it was scientifically independent, sponsored by the industries and governed by an international Scientific Advisory Committee (SAC). The present study is an individual evaluation of a subgroup of high consumers, per-formed by P.M. at the request of the German Drug Authority and the SAC.
Conflict of interest statement. The results presented in this paper have not
been published previously in whole or part in a peer-reviewed journal. A summary of the results has been published in [1]. L.H. was the Epi-demiological Principal Investigator and H.G was the Clinical Principal Investigator of the SAN study. K-M.K. was the chairman, and P.M., M.M. and P.S. were members of the SAC. None of the authors declared a conflict of interest.
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Received for publication: 15.5.08 Accepted in revised form: 21.10.08
